SoviHep 28Tabs

Sofosbuvir

Recommended Retail Price $200

Each tablet contains:

  • sofosbuvir 400 mg

Manufacturer: Zydus Heptiza, India

Distributor: Zydus Heptiza, India

 

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Description

Dosage Forms & Strengths

Tablet

  • 400mg

Hepatitis C Virus Infection

Indicated for treatment of chronic hepatitis C virus (HCV) infection as a component of a combination antiviral regimen for patients with HCV mono-infection and HCV/HIV-1 coinfection.

Treatment regimen and duration are dependent on both viral genotype and patient population.

Genotype 1 or 4: 400 mg PO qDay plus ribavirin and peginterferon alfa for 12 weeks; may consider sofosbuvir plus ribavirin for 24 weeks in genotype 1 patients ineligible to receive peg-interferon-based regimen.

Genotype 2: 400 mg PO qDay plus ribavirin for 12 weeks.

Genotype 3: 400 mg PO qDay plus ribavirin for 24 weeks.

Patients with hepatocellular carcinoma awaiting liver transplantation.

  • For prevention of post-transplant HCV reinfection.
  • 400 mg PO qDay plus ribavirin for up to 48 weeks or until the time of liver transplantation, whichever occurs first.

Ribavirin dosage regimen with sofosbuvir (genotypes 1, 2, 3, and 4).

  • Take with food.
  • <75 kg : 500 mg PO BID.
  • ≥75 kg: 600 mg PO BID.
  • Renal impairment (CrCl ≤50 mL/min): Reduce dose (see prescribing information).

Peginterferon alfa regimen with sofosbuvir (genotype 1 or 4).

  • Peginterferon alfa 2a: 180 mcg SC weekly.
  • Peginterferon alfa 2b: 1.5 mcg/kg/week SC; not to exceed 150 mcg/week.
  • Renal impairment (CrCl ≤50 mL/min): Reduce dose (see prescribing information).

Dosage Modification

Reduction of sofosbuvir dose not recommended.

Discontinue sofosbuvir therapy if the agents used in combination are discontinued.

Genotypes 1 and 4

  • Serious adverse reactions potentially related to peginterferon alfa and/or ribavirin: Should reduce or discontinue dose of peginterferon alfa and/or ribavirin following the recommendations of their respective prescribing information.

Genotypes 2 and 3

  • Serious adverse reaction potentially related to ribavirin: Modify or discontinue ribavirin dose.
  • Hemoglobin <10 g/dL without cardiac disease: Reduce ribavirin dose to 600 mg/day PO divided BID with food.
  • Hemoglobin <8.5 g/dL without cardiac disease: Discontinue ribavirin.
  • Cardiac disease and hemoglobin decreased ≥2 g/dL during 4 week period: Reduce ribavirin dose to 600 mg/day PO divided BID with food.
  • Cardiac disease and hemoglobin <12 g/dL despite 4 weeks at reduced dose: Discontinue ribavirin.
  • After discontinuing the dose may attempt to restart ribavirin at 600 mg PO divided bid and further increase it to 800 mg PO divided bid; increasing the dose to 1000-1200 mg/day not recommended.

Renal impairment

  • Mild or moderate: No adjustments required.
  • Severe (eGFR <30 mL/min/1.73 m²) or ESRD: No dosage recommendation can be given owing to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite.

Hepatic impairment

  • Mild, moderate, or severe (Child-Pugh Classes A, B or C): No dose adjustments required.
  • Decompensated cirrhosis: Not established.

Dosing Considerations

Efficacy has been established in combination with peginterferon alfa and ribavirin in HCV genotypes 1, 2, 3, and 4 infected subjects including hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 coinfection.

Must not be used as monotherapy; if peginterferon alfa or ribavirin is discontinued for any reason, sofosbuvir must also be discontinued.

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs).

Contraindications

Contraindications applicable to combination therapy.

Combination with ribavirin

  • Hypersensitivity
  • Pregnancy or planning pregnancy, including men whose female partners are pregnant/planning to get pregnant
  • CrCl <50 mL/min
  • Pancreatitis
  • Hemoglobinopathies (eg, thalassemia major, sickle cell anemia)
  • Coadministration with didanosine
  • Autoimmune hepatitis, decompensated liver disease (Child-Pugh class B, C)
  • Use in neonates, infants (contains benzyl alcohol)

Combination with peg-interferon alfa

  • Autoimmune hepatitis, decompensated liver disease (Child-Pugh class B, C)
  • Use in neonates, infants (contains benzyl alcohol)

Cautions

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV DDAs, and who were not receiving HBV antiviral therapy; HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level (see Black Box Warnings and Dosing Considerations).

Drugs that are potent P-gp inducers in the intestine (eg, rifampin, St. John’s wort) may significantly decrease sofosbuvir plasma concentrations.

Serious symptomatic bradycardia may occur in coadministration with amiodarone in combination with another direct acting antiviral (DAA), particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease; coadministration is not recommended, if no alternative exists, inpatient cardiac monitoring is recommended for the first 48 hr and then daily home monitoring for at least the first 2 weeks.

Must NOT be used as monotherapy.

Use with other drugs containing sofosbuvir not recommended.

Combination with ribavirin

  • Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients; patients must have a negative pregnancy test prior to therapy; use 2 or more forms of contraception, 1 of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone (lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated).
  • Risk of hemolytic anemia.
  • Anemia associated with treatment may result in worsening of cardiac disease.
  • Potential carcinogen effects.
  • Ocular disorders reported when ribavirin is used in combination therapy with alpha interferons (eg, decrease or loss of vision, retinopathy including macular edema, retinal artery or vein, thrombosis, retinal hemorrhages; cotton wool spots, optic neuritis, papilledema, serous retinal detachment).
  • Study in boys showed growth rate inhibited (ie, height percentile decreases) with peginterferon alfa-2b plus ribavirin.
  • Pancytopenia and bone marrow suppression reported when coadministered with pegylated interferon and azathioprine.

Combination with peg-interferon alfa

  • Discontinue STAT if progressive ALT increases despite dose reduction or accompanied with increased bilirubin or signs of hepatic decompensation.
  • Caution in renal impairment.
  • Risk of suicidal ideation and psychoses; discontinued if severe depression occurs.
  • Safety and efficacy not been established in patients with liver and other transplantations; as with other alpha interferons, liver and renal graft rejections have been reported.
  • May cause myelosuppression; discontinue therapy (at least temporarily) if platelet count <25,000/mm³ or ANC <500/mm³.
  • Will likely experience flu-like symptoms in early part of treatment.
  • May cause development of exacerbation of several pathologic conditions.
  • Reduce/discontinue if moderate/severe depression, see Manufacturer’s package insert.
  • In hepatic impairment, reduce/discontinue as suggested by Manufacturer’s package insert.

Pregnancy & Lactation

Pregnancy Category: B; Category X when used in combination with ribavirin or peginterferon alfa/ribavirin.

Sofosbuvir is coadministered with ribavirin and peginterferon alfa; extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated.

Women of childbearing potential and their male partners should not receive ribavirin or peginterferon alfa/ribavarin unless they are using effective contraception (2 reliable forms) during treatment with ribavirin and for 6 months after treatment; routine monthly pregnancy tests must be performed during this time.

Lactation: Unknown if distributed in human breast milk; take into account the importance of therapy to the mother when administered combination with ribavirin and/or peg-interferon alfa; because of the potential for adverse reaction, breastfeeding is not recommended.

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Pharmacology

Mechanism of Action

Nucleotide prodrug that undergoes metabolism to the active uridine analog triphosphate, an inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition in turn suppresses viral replication.

Pharmacokinetics

Absorption

  • Peak plasma time: 0.5-2 hr (sofosbuvir); 2-4 hr (metabolite GS-331007).
  • AUC when coadministered with ribavirin (with or without peg-interferon): 828 ng•hr/mL (sofosbuvir); 6790 ng•hr/mL (metabolite GS-331007).

Distribution

  • Plasma bound: 61-65% (sofosbuvir); minimal for metabolite GS-331007.

Metabolism

  • Liver
  • Substrate: P-gp transporter and breast cancer resistance protein (substrate for sofosbuvir but not metabolite GS-331007).

Elimination

  • Excretion: Urine (78% metabolite GS-331007; 3.5% sofosbuvir).
  • Half-life: 0.4hr (sofosbuvir); 27 hr (metabolite GS-331007).

Pharmacogenomics

Available data on genotype 5 or 6 HCV infection insufficient for dosing recommendations.

Genotype 2 or 3: Sustained virologic response (SVR): The response to the addition of peg-interferon alfa to the sofosbuvir/ribavirin combination therapy was not significantly different, in clinical trials, compared to the sofosbuvir/ribavirin combination alone.

Oral Administration

May take sofosbuvir with or without food.

Take ribavirin with food.

If the other agents used in combination with sofosbuvir are permanently discontinued, sofosbuvir should also be discontinued.

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